The basis for the severe immune compromise seen in the acquired immunodeficiency syndrome (AIDS) is the profound human immunodeficiency virus (HIV)-induced depletion of helper lymphocytes bearing the CD4 molecule. With improved anti-retroviral therapies, it has become increasingly obvious that the currently used surrogate markers, CD4 lymphocytes number and serum p24 antigen level, are not sensitive enough to permit a rapid assessment of the therapeutic response, particularly in asymptomatic or mildly affected patients. We propose to assess the immune response to biologically relevant HIV peptides using a quantitative assay which is a sensitive measure of immunologic function, i.e., the limiting dilution analysis. With this approach, a minimal estimate of the frequency of HIV peptide-reactive lymphocytes can be determined, using the secretion of interleukin 2 (IL-2) as an endpoint. It is known that one of the first immune functions to decline following HIV infection is the ability of T lymphocytes to proliferate in response to soluble antigens such as tetanus toxoid. We have obtained preliminary data showing that detectable frequencies of tetanus-reactive lymphocytes are present in asymptomatic, ARC, and AIDS patients, even when the ability of their T lymphocytes are present in asymptomatic, ARC, and AIDS patients, even when the ability of their T lymphocytes to proliferate to tetanus is lost. We now propose to extend this quantitative approach to assessment of HIV-peptide reactive lymphocytes. First, the frequency of lymphocytes responding by IL-2 secretion to four synthetic gp160 peptides will be determined in seronegative controls, asymptomatic, ARC, and AIDS patients. Secondly, the frequencies of lymphocytes responding to these peptides will be followed longitudinally in an asymptomatic patients group and correlated with clinical course, CD4 number, serum HIV p24 level, virus culture and general cellular immune function. In this manner, the relevance of the HIV- specific cellular immune response as a predictor of disease progression or response to therapy can be adequately assessed.